The present invention relates to new derivatives of amino acids and their use as medicaments. These derivatives have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or (according to preference):
either an activity which traps the reactive oxygen species (ROS);
or an antioxidant regenerating activity such as glutathione or reactive oxygen species (ROS) traps and more generally an influence on the redox status of the thiol groups.
Therefore the invention relates in particular to the derivatives corresponding to general formula (I) defined hereafter, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic ends, in particular their use as inhibitors of NO-synthases and/or (according to preference):
either as ROS traps;
or as agents allowing the regeneration of antioxidants such as glutathione or ROS traps entities and intervening in a more general fashion in the redox status of the thiol groups.
Given the potential role of NO, the ROS""s and the metabolism of glutathione in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where nitrogen monoxide, the ROS""s and the metabolism of glutathione as well as the redox status of the thiol groups are involved, and in particular:
cardiovascular and cerebrovascular disorders comprising, for example, atherosclerosis, migraine, arterial hypertension, septic shock, cardiac or cerebral infractions of ischemic or haemorrhagic origin, ischemias and thromboses;
disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where cerebral infarctions, sub-arachnoid haemorrhage, ageing, senile dementia, including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Freidreich""s ataxia, Creutzfeld-Jacob""s disease and prion diseases, amyotrophic lateral sclerosis, but also pain, cerebral or bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleeping disorders, eating disorders (anorexia, bulimia, etc.) can be mentioned in particular;
disorders of the skeletal muscle and of the neuromuscular junctions (myopathy, myositis) as well as skin diseases;
proliferative and inflammatory diseases such as, for example, atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastrointestinal system (colitis, Crohn""s disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities;
organ transplants;
auto-immune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies;
cancer;
autosomal genetic diseases such as Unverricht-Lundborg disease;
neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease)
impotence linked with diabetes;
all the pathologies characterized by a production or a dysfunction of nitrogen monoxide and/or ROS or the metabolism of glutathione and of the redox status of thiol groups.
In all these pathologies, there is experimental evidence demonstrating the involvement of nitrogen monoxide or of a dysfunction of the metabolism of glutathione (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology and Medicine 19, 227-250, 1995). In this context, medicaments which can inhibit the formation of nitrogen monoxide, trap the ROS""s or re-establish the biological functionality of the thiol groups or glutathione can have beneficial effects.
Compounds comprising both inhibitory properties of the NO-synthases and ROS trapping properties have already been described by the Applicant in earlier patent applications (cf. PCT Applications WO 98/42696, WO 98/58934, WO 00/02860, WO 00/17190 and WO 00/17191). More recently derivatives of lipoic acid having both inhibitory properties of the NO-synthases and regenerating properties of antioxidants or of ROS traps and more generally have an influence on the redox status of thiol groups have also been described more recently in the PCT Application WO 00/59899
The compounds of the invention correspond to general formula (I) 
in which
R1 represents a hydrogen atom or an alkyl radical;
A and Axe2x80x2 represent a hydrogen atom or one of the following radicals:
a 
xe2x80x83radical, in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or NR8R9 radical,
R8 and R9 representing, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR10 group,
or R8 and R9 form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R10 representing a hydrogen atom, an alkyl, alkoxy or NR11R12 radical,
R11 and R12 representing, independently, a hydrogen atom or an alkyl radical,
or R11 and R12 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R7 represents a hydrogen atom, an alkyl radical or a xe2x80x94COR13 group,
R13 representing a hydrogen atom, an alkyl or alkoxy or NR14R15 radical,
R14 and R15 representing independently, a hydrogen atom or an alkyl radical, or R14 and R15 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
and xcexa9 does not exist, or represents a bond, O or S or also an NR16 radical, in which R16 represents a hydrogen atom or an alkyl radical;
or a 
xe2x80x83radical, in which R17, R18 and R19 represent, independently, a hydrogen, a halogen, the OH or SR20 group or an alkyl, alkenyl or alkoxy radical or an NR21R22 radical,
R20 representing a hydrogen atom or an alkyl radical,
R21 and R22 representing, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR23 group,
or R21 and R22 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R23 representing a hydrogen atom, an alkyl, alkoxy or NR24R25 radical,
R24 and R25 representing, independently, a hydrogen atom or an alkyl radical, or R24 and R25 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
and Q represents xe2x80x94OR26, xe2x80x94SR26 or a phenyl radical substituted by one or more substituents chosen from a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or NR8R9 radical,
R26 representing a hydrogen atom or an alkyl radical,
R8 and R9 representing, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR10 group,
or R8 and R9 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R10 representing a hydrogen atom, an alkyl, alkoxy or NR11R12 radical,
R11 and R12 representing, independently, a hydrogen atom or an alkyl radical, or R11 and R12 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
or a 
xe2x80x83radical in which R27 represents a hydrogen atom, an alkyl radical or an aralkyl radical, T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or a 
xe2x80x83radical in which R28 represents a hydrogen atom, an alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or aralkyl radical the aryl group of which is optionally substituted by one or more substituents chosen independently from the OH group, a halogen atom, an alkyl, alkoxy, nitro or xe2x80x94NR29R30 radical, in which R29 and R30 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR31 group, or R29 and R30 form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R31 representing a hydrogen atom, an alkyl or alkoxy or NR32R33 radical,
R32 and R33 representing, independently, a hydrogen atom or an alkyl radical, or R32 and R33 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or a 
xe2x80x83radical in which R34 and R35 represent independently a hydrogen atom or an alkyl or aralkyl radical the aryl group of which is optionally substituted by one or more substituents such as the OH group, the alkyl, halogen, nitro, alkoxy or xe2x80x94NR36R37 radicals, in which R36 and R37 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR38 group, or R36 and R37 form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
R38 representing a hydrogen atom, an alkyl or alkoxy or NR39R40 radical,
R39 and R40 representing, independently, a hydrogen atom or an alkyl radical, or R39 and R40 forming together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or a 
xe2x80x83radical in which R41 represents a hydrogen atom, the OH group, or an alkyl or alkoxy radical;
or finally a 
xe2x80x83D represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S and N (and in particular the thiophene, furane, pyrrole or thiazole radicals), the carbocyclic or heterocyclic aryl radical being optionally substituted by one or more groups chosen independently from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
or D represents an NR42R43 radical, in which R42 and R43 represent, independently, a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical having 1 to 6 carbon atoms or a cyano, nitro or amino radical, or R42 and R43 form together with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain being chosen from a group comprising xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
or also D represents an xe2x80x94SR44 radical, in which R44 represents a linear or branched alkyl radical having 1 to 6 carbon atoms optionally substituted by a group chosen from: xe2x80x94OH, halogen, amino, cyano and aralkyl;
X represents a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94, xe2x80x94Sxe2x80x94(CH2)pxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)pxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94COxe2x80x94 radical,
n being an integer from 0 to 6
and p being an integer from 1 to 6;
W represents xe2x80x94Oxe2x80x94 or xe2x80x94NR45xe2x80x94,
and R45 representing a hydrogen atom or an alkyl radical;
Y represents a radical chosen from xe2x80x94(CH2)txe2x80x94, xe2x80x94(CH2)qxe2x80x94Oxe2x80x94, xe2x80x94(CH2)qxe2x80x94Sxe2x80x94 and xe2x80x94(CH2)qxe2x80x94NR46xe2x80x94 and R46 representing a hydrogen atom or an alkyl radical,
t being an integer from 0 to 6
and q being an integer from 2 to 6;
V represents a radical chosen from the xe2x80x94(CH2)rxe2x80x94, xe2x80x94(CH2)rxe2x80x94Oxe2x80x94(CH2)sxe2x80x94, xe2x80x94(CH2)rxe2x80x94Sxe2x80x94(CH2)sxe2x80x94, xe2x80x94(CH2)rxe2x80x94S(O)xe2x80x94(CH2)sxe2x80x94 and xe2x80x94(CH2)rxe2x80x94S(O)2xe2x80x94(CH2)sxe2x80x94 radicals
r being an integer from 1 to 6,
s being an integer from 2 to 6;
it being understood that one of A and Axe2x80x2 represents a hydrogen atom and the other does not represent a hydrogen atom;
or are salts of the compounds of general formula (I) as defined above.
These compounds have an inhibitory activity on the NO-synthase enzymes producing nitrogen monoxide NO and/or (according to preference):
either an activity which traps the reactive oxygen species (ROS) when neither A nor Axe2x80x2 represents the 
radical;
or a regenerative activity on antioxidants or entities which trap the reactive oxygen species (ROS) and more generally an influence on the redox status of the thiols group, in the particular case where one of A and Axe2x80x2 represents the 
xe2x80x83radical.
By alkyl, unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 12 carbon atoms, and preferably 1 to 6 carbon atoms. By alkenyl, unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being referred to as heterocyclic when at least one of the rings which compose it contains a heteroatom (O, N or S). By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom.
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals the alkyl radical of which has the meaning indicated previously.
By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. Finally, by halogen is meant the fluorine, chlorine, bromine or iodine atoms.
In certain cases, the compounds according to the present invention can contain asymmetrical carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. the xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the racemic xe2x80x9cRSxe2x80x9d mixtures. In a effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
In the general formula (I), when A or Axe2x80x2 represents the 
radical, R27 will preferably represent a hydrogen atom or an alkyl radical and T will preferably represent the xe2x80x94(CH2)2xe2x80x94 radical.
Furthermore, when A or Axe2x80x2 represents the 
radical, R34 and R35 will preferably represent radicals selected independently from a hydrogen atom and an alkyl radical and T will preferably represent the xe2x80x94(CH2)xe2x80x94 radical.
Also preferably, the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
an A or Axe2x80x2 group representing one of the following radicals:
either the 
xe2x80x83radical in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R7 represents a hydrogen atom and xcexa9 does not exist or represents a bond or S;
or the 
xe2x80x83radical in which Q represents xe2x80x94OR26 or xe2x80x94SR26 and R17, R18 and R19 represent independently a hydrogen atom, the OH, SR20 or NR21R22 group or an alkyl or alkoxy radical,
R26 representing a hydrogen atom or an alkyl radical,
R20 representing a hydrogen atom or an alkyl radical,
and R21 and R22 representing, independently, a hydrogen atom or an alkyl radical;
or the 
xe2x80x83radical in which R28 represents a hydrogen atom or an alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or aralkyl radical the aryl group of which is optionally substituted by one or more radicals chosen independently from an alkyl radical and the xe2x80x94NR29R30 radical in which R29 and R30 represent, independently, a hydrogen atom or an alkyl radical,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or finally the 
xe2x80x83radical;
D representing a carbocyclic or heterocyclic aryl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S and N, the carbocyclic or heterocyclic aryl radical being optionally substituted by one or more groups chosen independently from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
or also D representing an NR42R43 radical, in which R42 and R43 represent, independently, a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical having 1 to 6 carbon atoms or a cyano, nitro or amino radical, or R42 and R43 form together with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain being chosen from a group comprising xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
V representing a xe2x80x94(CH2)rxe2x80x94, xe2x80x94(CH2)rxe2x80x94Oxe2x80x94(CH2)sxe2x80x94 or xe2x80x94(CH2)rxe2x80x94Sxe2x80x94(CH2)sxe2x80x94 radical, r being an integer from 1 to 6 and s an integer from 2 to 6;
W representing xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
X representing a xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94 or xe2x80x94Sxe2x80x94(CH2)pxe2x80x94 radical, n being an integer from 0 to 6 and p an integer from 1 to 6;
Y representing a radical chosen from xe2x80x94(CH2)txe2x80x94, xe2x80x94(CH2)qxe2x80x94Oxe2x80x94 and xe2x80x94(CH2)qxe2x80x94NR46xe2x80x94, R46 representing a hydrogen atom or an alkyl radical, t representing an integer from 0 to 6 and q an integer from 2 to 6.
More preferentially, the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
an A or Axe2x80x2 group representing one of the following radicals:
either the 
xe2x80x83radical in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R7 represents a hydrogen atom and xcexa9 does not exist or represents a bond or S;
or the 
xe2x80x83radical in which xcexa9 represents OH and R17, R18 and R19 represent independently a hydrogen atom, the OH, SR20 or NR21R22 group or an alkyl radical or alkoxy,
R20 representing an alkyl radical,
R21 and R22 representing, independently, a hydrogen atom or an alkyl radical;
or the 
xe2x80x83radical in which R28 represent an alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or aralkyl radical;
or finally the 
xe2x80x83radical;
D representing a heterocyclic aryl radical with 5 members containing 1 to 4 heteroatoms chosen from O, S and N,
or also D representing an NR42R43 radical, in which R42 and R43 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a nitro radical, or R42 and R43 form together with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain being chosen from a group comprising xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
V representing a xe2x80x94(CH2)rxe2x80x94 radical, r being an integer from 1 to 6;
W representing xe2x80x94NHxe2x80x94;
X representing a xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94 radical, n being an integer from 0 to 6;
Y representing a radical chosen from xe2x80x94(CH2)txe2x80x94, xe2x80x94(CH2)qxe2x80x94Oxe2x80x94 and xe2x80x94(CH2)qxe2x80x94NHxe2x80x94, t representing an integer from 0 to 6 and q an integer from 2 to 6.
Yet more preferentially, the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
an A or Axe2x80x2 group representing one of the following radicals:
either the 
xe2x80x83radical in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R7 represents a hydrogen atom and xcexa9 does not exist or represents a bond or S;
or the 
xe2x80x83radical in which Q represents OH and two of R17, R18 and R19 represent alkyl radicals, the third being chosen from a hydrogen atom and an alkyl, alkoxy or alkylthio radical;
or the 
xe2x80x83radical in which R28 represents an alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical;
or finally the 
xe2x80x83radical;
D representing the xe2x80x94NHxe2x80x94NO2. radical
V representing a xe2x80x94(CH2)rxe2x80x94 radical, r being an integer from 1 to 5 and preferably an integer from 2 to 4;
Y representing a xe2x80x94(CH2)txe2x80x94 radical, t representing an integer from 0 to 6.
In particular, a subject of the invention is the following compounds described in the examples:
-(2S)-2-amino-N-(4-anilinophenyl)-5-{[imino(2-oxido-2-oxohydrazino)methyl]amino}pentanamide;
-(2S)-2-amino-5-{[imino(2-oxido-2-oxohydrazino)methyl]amino}-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)pentanamide;
-(2S)-2-[(3,5-ditert-butyl-4-hydroxybenzyl)amino]-5-{[imino(2-oxido-2-oxohydrazino)methyl]amino}pentanoic acid;
-methyl (2S)-2-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}-5-{[imino(2-oxido-2-oxohydrazino)methyl]amino}pentanoate;
-(2S)-2-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}-5-{[imino(2-oxido-2-oxohydrazino)methyl]amino}pentanoic acid;
as well as their salts.
A subject of the invention is also, as medicaments, the compounds of general formula (I) described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, with one or more pharmaceutically acceptable excipients. It also relates to the use of these compounds or of their pharmaceutically acceptable salts to produce the medicaments intended:
1) to inhibit neuronal NO synthase or inductible NO synthase; to inhibit lipidic peroxidation; or finally to provide the dual function of inhibition of NO synthase and inhibition of lipidic peroxidation, when neither A nor Axe2x80x2 represents the 
xe2x80x83radical;
2) to inhibit neuronal NO synthase or inductible NO synthase; to regenerate antioxidants or ROS trapping entities and more generally to intervene in the redox status of the thiols group; or finally to provide the dual function of inhibition of NO synthase and regeneration of antioxidants or entities which trap ROS and more generally to intervene in the redox status of the thiols group, when the one of A and Axe2x80x2 represents the 
xe2x80x83radical.
Preferably, the compounds of general formula (I) as previously defined or the pharmaceutically acceptable salts of such compounds will be used for preparing a medicament intended to treat cardiovascular and cerebrovascular disorders or central or peripheral nervous system disorders.
By pharmaceutically acceptable salt is meant in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate. Also within the scope of the present invention, when they can be used, are the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cSalt selection for basic drugsxe2x80x9d, Int. J. Pharm. (1986), 33, 201-217.
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound according to the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
Administration of a medicament according to the invention can be carried out by topical, oral, parenteral route, by intramuscular injection, etc.
The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg and 10 g depending on the type of active compound used.
According to the invention, the compounds of general formula (I) can be prepared using the processes described hereafter.
Preparation of the Compounds of General Formula (I)
The compounds of general formula (I) can be prepared according to different synthesis strategies which are described in the following diagrams: 
The aminocarboxamides of general formula (I), Diagram 1, in which Axe2x80x2, D, V, Y and R1 are as defined above with, in particular, A representing a hydrogen atom, X a (xe2x80x94(CH2)nxe2x80x94 bond with n=0) and Wxe2x95x90xe2x80x94NR45xe2x80x94 are prepared in two stages, from the protected amino acids (Gp1 being a protective group of carbamate type) of general formula (III) and the amines of general formula (IV). Their condensation is carried out under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane, pyridine or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) in order to produce the carboxamides of general formula (II). Cleavage of the protective group Gp1 is then carried out in a standard fashion, for example in the presence of a strong acid, of a secondary amine or under conditions of hydrogenolysis, according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce the final compounds of general formula (I). The syntheses of the non-commercial compounds of general formula (III) and (IV) are described below.
B) Alternatively the derivatives of amino acids of general formula (I) can be prepared according to the strategy described in Diagram 2, in which A, D, V and R1 are as defined above with Axe2x80x2 representing a hydrogen atom, Wxe2x95x90xe2x80x94Oxe2x80x94, Yxe2x95x90xe2x80x94(CH2)txe2x80x94 (t=0), Xxe2x95x90xe2x80x94(CH2)nxe2x80x94, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94, xe2x80x94Sxe2x80x94(CH2)pxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 (CH2)pxe2x80x94(n being in this case an integer from 1 to 6) and Gp2 being an alkyl or arylalkyl group. 
The derivatives of aminoesters of general formula (V) are accessible, during a reducing amination stage, by condensation of the aldehydes of general formula (VI) and of the xcex1-aminoesters of general formula (VII). This condensation is carried out in a standard fashion at 20xc2x0 C. in an alcoholic solvent such as methanol in the presence of a dehydration agent, such as molecular sieves, and of a reducing agent such as, for example, NaBH3CN. This stage leads to the mono-alkylation product of general formula (V). Deprotection of the acid function is then carried out in a standard fashion according to the nature of Gp2, for example, by saponification using LiOH or according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce the amino acids of general formula (I). The syntheses of the non-commercial compounds of general formula (VI) and (VII) are described below.
C) Moreover, the carboxamides of general formula (I) can also be prepared according to the strategy described in Diagram 3, in which A, D, V and R1 are as defined above with Axe2x80x2 representing a hydrogen atom, Wxe2x95x90xe2x80x94Oxe2x80x94, Yxe2x95x90xe2x80x94(CH2)txe2x80x94 (t=0), Xxe2x95x90xe2x80x94(CH2)nxe2x80x94COxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94COxe2x80x94 (n being an integer from 0 to 6) and GP2 being an alkyl or arylalkyl group. 
Condensation of the carboxylic acids of general formula (IX) with the xcex1-aminoesters of general formula (VII) is carried out under standard conditions for peptide synthesis as previously described. The carboxamide ester of general formula (VIII) obtained intermediately is then deprotected according to a protocol described in Diagram 2 in order to produce the carboxamide acids of general formula (I). The syntheses of the non-commercial compounds of general formula (IX) are described below.
Preparation of the Intermediates of General Formula (III)
The compounds of general formula (III) can be prepared from the intermediates of general formula (III.2) according to Diagram 1.1 where D, V and R1 are as defined above, Gp1 being a protective group of carbamate type and Gp2 is an alkyl or arylalkyl group. 
The amines of general formula (III.2) can be condensed with compounds of general formula (III.3), in which L represents a parting group (an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical), by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF, at a temperature comprised between 20 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight, in order to produce the intermediates of general formula (III.8).
In the case where D is an amine, the intermediates of general formula (III) are guanidines. These can be prepared, for example, by the condensation of the amines of general formula (III.2) with the derivatives of general formula (III.5) or (III.6). The reagents of general formula (III.5) in which L represents, for example, a pyrazole ring are condensed with the amines of general formula (III.2) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502) similarly for the reagents of general formula (III.6) in which L represents, for example, a pyrazole ring and Gp represents the Boc group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp represents the Boc group (J. Org. Chem. (1998) 63, 3804-3805). The deprotection of the guanidine function can then be carried out, for example, in the presence of a strong acid such as for example trifluoroacetic acid in order to produce the intermediates of general formula (III.8).
In the case where Dxe2x95x90xe2x80x94NHNO2, the intermediates of general formula (III.8) can be prepared, for example, by the condensation of the amines of general formula (III.2) with the reagent of general formula (III.7) (N-methyl-Nxe2x80x2-nitro-N-nitrosoguanidine) according to the conditions described in the literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).
In the case where D is an xe2x80x94SR44 radical, the isothiourea derivatives of general formula (III.8) are prepared in 3 stages from the primary amine of general formula (III.2). The reaction of the benzoylisothiocyanate on the amine of general formula (III.2) in a solvent such as, for example, acetone, leads to the benzoyl-thiourea intermediates which are then hydrolysed in a standard fashion by heating in a basic medium. The thioureas thus obtained are then alkylated by a halogenated derivative R44-Hal, by heating in an inert solvent, in order to produce the isothioureas of general formula (III.8).
The deprotection of the acid function of the intermediates of general formula (III.8) is then carried out in a standard fashion according to the nature of Gp2, for example, by saponification using LiOH or according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).
Preparation of the Intermediates of General Formula (IV)
A) When Axe2x80x2 is as defined above, Wxe2x95x90xe2x80x94NR45xe2x80x94 and Yxe2x95x90xe2x80x94(CH2)txe2x80x94(t=0), the amines of general formula (IV) are prepared according to the following synthesis strategies:
The non-commercial anilines of general formula (IV), derivatives of indoline or of 1,2,3,4-tetrahydroquinoline, Diagram 2.1, in which T and R28 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (IV.1). 6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J. Chem. (1952), 30, 720-722. Alkylation of the amine is carried out in a standard fashion by a strong base such as, for example, NaH, in a polar aprotic solvent such as, for example, DMF in the presence of a halogenated derivative R28-Hal, such as for example, 3-dimethylaminopropane chloride or benzyl bromide. The nitro derivative of general formula (IV.2) obtained intermediately is then reduced, for example, by Raney nickel in the presence of hydrazine hydrate in order to produce anilines of general formula (IV). 
In the particular case of phenolic derivatives, the anilines of general formula (IV) are obtained by hydrogenation, in the presence of Pd/C, from the precursor nitrophenol derivatives. The nitrated derivatives of the di-alkylphenols are accessible according to a method described in J. Org. Chem. (1968) 33 (1), 223-226.
The intermediates of general formula (IV) in which Axe2x80x2 is a diphenylamine are accessible by the methods described in the literature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18(4), 386-391) which involve the reduction of a nitrodiphenylamine intermediate. Reduction of the nitro function is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in order to access the aminodiphenylamines of general formula (IV).
When Axe2x80x2 is a carbazole derivative (xcexa9 then represents a direct bond), the methods for preparation of the aminocarbazoles of general formula (IV) involve the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48(11), 817-820; Synth. Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org. Chem. (1964) 29(8), 2474-2476; Org. Prep. Proced. Int. (1981) 13(6), 419-421 or J. Org. Chem. (1963) 28, 884. Reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney nickel.
The intermediates of general formula (IV) in which Axe2x80x2 is a phenothiazine derivative (xcexa9 represents a sulphur atom), are accessible using the methods of the literature which involve the synthesis of a nitrophenothiazine derivative. In particular, 3-nitrophenothiazine is described in J. Org. Chem. (1972) 37, 2691. Reduction of the nitro function in order to access the aminophenothiazines of general formula (IV) is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in a solvent such as ethanol.
B) Alternatively, when Yxe2x95x90xe2x80x94(CH2)qxe2x80x94Oxe2x80x94 and Wxe2x95x90xe2x80x94NR45xe2x80x94, the amines of general formula (IV), Diagram 2.2 (in which Alk represents an alkyl radical), can be prepared from the hydroquinones of general formula (IV.3) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). Condensation on the commercial halogen esters of general formula (IV.4) is carried out in the presence of a base such as, for example K2CO3, while heating in a polar solvent such as, for example, THF for at least 5 hours. The esters of general formula (IV.5) obtained intermediately are then deprotected (in an acid medium in the case of the tert-butyl esters) in order to produce the acids of general formula (IV.6). The primary carboxamides of general formula (IV.7) are prepared using a concentrated aqueous solution of ammonium hydroxide, of DCC and HOBT in a solvent such as DMF. The reduction stage is carried out in an anhydrous medium, by heating to 70-80xc2x0 C., in the presence of a selective reagent of carboxamides such as, for example, BH3.THF, in a solvent such as, for example, THF in order to produce the amines of general formula (IV). 
C) Moreover, when Yxe2x95x90xe2x80x94(CH2)txe2x80x94 (with t xe2x89xa00) and Wxe2x95x90xe2x80x94NR45xe2x80x94, the amines of general formula (IV), Diagram 2.3, are also accessible, for example, in two stages from the carboxylic acids of general formula (IV.8) according to a strategy similar to that described in Diagram 2.2 for intermediate (IV.6). The syntheses of the non-commercial carboxylic acids of general formula (IV.8) are described in the section on Preparation of the intermediates of general formula (IX). 
Preparation of the Intermediates of General Formula (VI)
A) When A is as defined above and Xxe2x95x90xe2x80x94(CH2)nxe2x80x94 or Xxe2x95x90xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)pxe2x80x94 with n=1 or p=1, the aldehydes of general formula (VI) can be prepared from the nitrites or the corresponding carboxylic esters during a reduction stage in the presence, for example, of DIBAL or of another boron derivative, in an anhydrous solvent such as, for example, THF or dichloromethane, at a temperature varying from xe2x88x9278xc2x0 C. to 20xc2x0 C. Certain aldehydes are also accessible using methods described in the literature: Bull. Chem. Soc. Jpn. (1978) 51 (8), 2433-2434, Bioorg. Med. Chem. Lett. (1998) 8, 3453-3458.
B) Alternatively, when A is as defined above and Xxe2x95x90xe2x80x94Oxe2x80x94(CH2)pxe2x80x94, the aldehydes of general formula (VI), Diagram 3.1 (in which Alk represents an alkyl radical), can be prepared from the hydroquinones of general formula (VI.1) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). Condensation with commercial halogen esters of general formula (VI.2) is carried out under the conditions previously described (Diagram 2.2) as well as the reduction of the ester to an aldehyde (paragraph A). 
Preparation of the Intermediates of General Formula (VII)
The compounds of general formula (VII), Diagram 4.1, can be prepared from the intermediates of general formula (III.8), described in Diagram 1.1, where D, V and R1 are as defined above, Gp1 being a protective group of carbamate type and Gp2 is an alkyl or arylalkyl group. Deprotection of the amine function is carried out in a standard fashion depending on the nature of Gp1, for example, using a strong acid, such as for example 4N HCl in dioxane, or according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). 
Preparation of the Intermediates of General Formula (IX)
The non-commercial acids of general formula (IX) are accessible using the methods in the literature. For example, trisnorlipoic acid [2-(1,2-dithiolan-3-yl) acetic acid] is obtained in 5 stages according to an experimental protocol described in Tetrahedron Letters. (1997), 38 (33), 5785-5788. The syntheses of the acids derived from phenothiazine are in particular described in J. Med. Chem. (1998), 41(2), 148-156 or Bull. Soc. Chim. Fr. (1960), 1049-1066.
Unless otherwise defined, all the technical and scientific terms used here have the same meanings as those generally understood by the ordinary specialist in the field to which this invention belongs. Similarly, all the publications, patent applications, all patents and all other references mentioned here are incorporated by way of reference.